Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of neuroleptic drugs which primarily exert their effect via antagonism of D2 receptors are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that selective antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine which exerts higher affinity for D4 than D2 receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507–526, and Sanner Exp. Opin. Ther. Patents 1998, 8, 383–393).
A number of D4 ligands which were postulated to be selective D4 receptor antagonists (L-745,879 and U-101958) have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194–200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889–896 and Gazi et al. Br. J Pharmacol. 1999, 128, 613–620). Furthermore, it was shown that clozapine, which is an effective antipsychotic is a silent D4 antagonist (Gazi et al. Br. J Pharmacol. 1999, 128, 613–620).
Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78–84).
It has also been suggested that selective dopamine D4 antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson's disease with L-dopa (Tahar et al. Eur. J. Pharmacol. 2000, 399, 183–186).
Furthermore, evidence for a genetic association between the “primarily inattentive” subtype of attention deficit hyperactivity disorder and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol. Psychiat. 2000, 5, 531–536). This clearly indicates a link between the dopamine D4 receptor and attention deficit hyperactivity disorder and ligands affecting this receptor may be useful for the treatment of this particular disorder
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of psychoses, the positive symptoms of schizophrenia, cognitive deficits, attention deficit hyperactivity disorder (ADHD) and dyskinesia resulting from treatment of Parkinson's disease with L-Dopa.
In particular, the compounds of the invention are considered useful in the treatment of positive symptoms of schizophrenia without inducing extrapyramidal side effects.
A number of dopamine D4 ligands which can be described by the general formula
wherein Het is 3-pyrrolo[2,3-b]pyridinyl, 2-benzimidazolyl, 3-indazolyl, 2-indolyl, 3-indolyl, 3-benzofuranyl, imidazo[1,2-a]pyridinyl, 3-furo[2,3-b]pyridinyl and 3-benzofuranyl and Ar is optionally substituted phenyl or heteroaryl, have been described in WO 94/20459, WO 94/20497, WO 94/22839, WO 94/21630, WO 94/24105, WO 99/09025, WO 95/29911, WO 96/25414, U.S. Pat. No. 5,700,802 and J. Med. Chem. 1996, 39(19), 1941–2.
EP patent application No. 164 633 relates to compounds of the formula
wherein Ar is optionally substituted phenyl or thienyl, n is 2–4 and Ind is optionally substituted 4-indolyl. The compounds are said to inhibit binding of dopamin agonists and -antagonists to striatal receptors and to have sedative, tranquilizing, antidepressive neuroleptic, analgetic and antihypertensive effect. The application does not present any biological test results.
EP patent No. 372 667 relates to compounds having the formula
wherein Ar is 2-methoxyphenyl or 1-napthyl, n is 2–4 and R is various heterocyclic rings, e.g. 5-oxindole. The compounds are said to have neuroleptic activity, and data showing the ability of the compounds to bind to dopamine D2 receptors are presented in the application.
EP patent No. 0 281 309 describes certain piperazinyl-heterocyclic compounds of the formula
wherein A together with the phenyl to which it is attached form quinolyl, 2-hydroxyquinolyl, benzothiazolyl, 2-aminobenzothiazolyl, benzisothiazolyl, indazolyl, 3-hydroxyindazolyl, indolyl, etc., and Ar is optionally substituted naphthyl, quinolyl, isoquinolyl, indolyl, etc. Notably n is 1 or 2. The compounds are said to be useful for the treatment of psychoses and the mechanism of action is primarily via modulation of the dopamine D2-receptor, the serotonin 5-HT2A-receptor and the alpha-adrenergic receptor (J. Med. Chem. 1996, 39, pp.143–148).
According to the present invention, a novel group of compounds which are selective dopamine D4 ligands is provided.